68Ga is of special interest for the production of Ga-radiolabelled metal complexes used as radiotracer molecules in PET imaging in vivo. 68Ga is obtained from a 68Ge/68Ga generator, which means that no cyclotron is required. 68Ga decays 89% by positron emission of 2.92 MeV, and its 68 min half-life is sufficient to follow many biochemical processes in vivo without unnecessary radiation dose to the patient. In the oxidation state of Ga(III), 68Ga forms stable metal complexes with various types of chelating agents and 68Ga tracers have been used for brain, renal, bone, blood pool, lung and tumour imaging.
The use of 68Ga from a 68Ge/68Ga generator for the production of 68Ga-radiolabelled metal complexes used as PET tracer molecules does, however, have some difficulties. Thus, 68Ga eluate from a 68Ge/68Ga generator often contains 68Ge which leads to low radionuclide purity of 68Ga-radiolabelled metal complexes produced from the 68Ga eluate. Furthermore, the eluate also contains so-called pseudo carriers, i.e. other metal cations like Fe3+, Al3+, Cu2+, Zn2+ and In3+, which compete with 68Ga3+ in the subsequent metal complex formation reaction and eventually decrease the specific activity. A further disadvantage is that 68Ga eluate from a 68Ge/68Ga generator has a low 68Ga concentration, i.e. in the picomolar to nanomolar range. Consequently, the amount of chelating agent in a subsequent 68Ga-radiolabelling reaction has to be high for the reaction to take place, which in turn leads to low specific activity. A high amount of chelating agent is especially problematic with 68Ga-radiolabelled PET radiotracers that comprise a bifunctional chelating agent, i.e. a chelating agent linked to a targeting vector are produced as the patient will receive an unfavourably high amount of these tracers.
J. Schuhmacher et al. [Int. J. Appl. Radiat. Isotopes 32, 31-36 (1981)] describe the use of a Bio-Rad AG 1×8 anion exchanger for treating the 4.5 N HCl 68Ga eluate obtained from a 68Ge/68Ga generator in order to decrease the amount of 68Ge present in the eluate. 4 mL water was used to eluate the anion exchanger. A disadvantage of this method is the high volume of water necessary to elute the 68Ga from the anion exchanger. In order to use this eluate for the production of 68Ga-radiolabelled PET tracers that comprise a bifunctional chelating agent, the eluate needs to be further concentrated, e.g. by evaporation which in turn leads to a decrease of 68Ga activity due to the short half-life of this radionuclide.
Velikyan et al [Bioconj. Chem., 15, 554-560 (2004) and WO 2004/089517] disclose an improved method of obtaining 68Ga, which involves the use of an anion exchange resin comprising HCO3− counterions. The Velikyan method for the pre-concentration and purification of the generator eluate is based on anion exchange chromatography and the formation of gallium tetrachloride anion using 4M hydrochloric acid. However, the strong hydrochloric acid used for the acidification is corrosive and hazardous.
The availability of the 68Ga in pure and concentrated form remains as key requirement for the production of radiotracers with sufficiently high specific radioactivity allowing accurate quantification of PET data.